PROJECT SUMMARY Comorbidities between different mood disorders, as well as those with other syndromes such as schizophrenia, PTSD, and OCD suggest the possibility of shared underlying mechanisms that could inform development of new treatments. However, a rate-limiting step in uncovering such mechanisms continues to be the difficulty of studying these disorders in laboratory animals: it may never be possible to look at the behavior of an animal and know that it is experiencing a mood disorder. To side-step this fundamental challenge, we take a different approach: we will establish a neural assay of negatively biased thought. Many mood disorders are characterized by biased information processing, including recall biases for negative past events (in major depression) and biases towards generating negative future scenarios (in generalized anxiety disorder). Cognitive process theories of learning, memory and decision-making indicate that such biased thought may not only be a signature of mood disorders, but in fact causally contribute to it. This work will develop a neural assay of negatively biased thought in mice by focusing on sharp wave-ripples (SWRs): bursts of internally generated, synchronous neural activity in the hippocampus that can depict past or upcoming experiences. SWRs are an attractive preclinical target because (1) SWRs are highly conserved across mammals including rodents and humans, making it likely that results will translate, and (2) SWR activity can be decoded to reveal their content, such as retrieval of specific prior experiences. This implies that we can establish an objective neural assay for negatively biased thought: given a positive and a negative experience, are both experiences retrieved equally often, equally effective downstream, or is there a bias? Aim 1 will optimize a behavioral task and neural assay to provide positive and negative experiences that can be neurally distinguished, yielding for individual subjects and individual recording sessions a SWR content bias for negative compared to positive events. Next, Aim 2 will administer drugs known to generate affectively biased information processing in rodents in humans (amphetamine and pramipexole) and determine their effects on SWR bias and behavior. Finally, we will probe the mechanisms that link SWR content to motivational/affective systems at the neural circuit level through their interaction with dopamine in Aim 3. Taken together, the proposed work is expected to establish SWR content as a candidate transdiagnostic process that is of broad relevance to a number of mental health disorders.